Bioabsorbable polymers with stability at ambient conditions, and high melting and softening temperatures are highly prized for various medical and pharmaceutical applications. Polymers that incorporate non-toxic, naturally occurring monomers into the polymer backbone are also preferred for such applications.
One class of α-amino acid-based polymers is poly(ester ureas) (PEUs), which are prepared from bis(α-aminoacyl)-α,ω-diol-diester monomers. Monomer contains two ester linkages per molecule, which can undergo either nonspecific (chemical) or specific (enzymatic) hydrolysis. The first attempt to use of this type of monomers (diamine monomers of α-amino acids in the form of bis(α-aminoacyl)-α,ω-diol-diester) for preparing bioabsorbable, semi-physiological PEUs was made in the late 1970s by S. J. Huang et al. (J. Appl. Polym. Sci, (1979) 23:429-437) and yielded a low molecular weight powdery polymer with Mn of 2000 Da and melting points in the range from 191-199° C. Hydrolytic degradation of these PEUs with various enzymes was also reported.
Later, Yoneyama et al. reported the synthesis of high molecular weight semi-physiological PEUs by the same route: Interaction of free bis(α-aminoacyl)-alkylene-diesters with non-physiological diisocyanates (Polym. Prepr. Jpn. (1994) 43:177). In some cases, high molecular weight PEUs were obtained with viscosities up to 0.7 dL/g.
Lipatova et al. have also synthesized semi-physiological poly(ester urethane ureas) from bis(L-phenylalanyl)-alkylene-diesters, diols and diisocyanates (Lipatova T. E. et al., Dokl. Akad. Nauk SSSR (1980) 251(2):368 and Gladyr II, et al. Vysokomol. Soed. (1989) 31B(3):196). However, no information on the synthesis of the starting material (for example., α-diamino diesters) was provided.
In 1997, Katsarava et al. (Kartvelishvili T, et al. Macromol. Chem. Phys. (1997) 198:1921-1932) published an account of synthesizing homo-PEUs (without using diisocyanates,) via active polycondensation, a process in which active carbonates (e.g. di-p-nitrophenyl carbonate) were interacted with di-p-toluenesulfonic acid salts of bis(α-amino acid)-α,ω-alkylene diesters. In this case, low-molecular-weight polymers were obtained. The low molecular weight of these polymers was attributed to intramolecular cyclization, resulting in hydantoin formation and, therefore, chain scission. Hydantoins are known as biocides. Biodegaradable PEUs containing hydantoin cycles may also possess innate antimicrobial activity.
Currently, however, modern research is aimed at investigating biodegradable polymer systems. These drug deliverers degrade into biologically acceptable compounds, often through the process of hydrolysis, and leave their incorporated medications behind. This erosion process occurs either in bulk (for example in case of poly(anhydrides), wherein the matrix degrades uniformly) or at the polymer's surface (whereby release rates are related to the polymer's surface area). The degradation process of well known aliphatic polyesters, PLLA or PLGA, involves the breakdown of these polymers into lactic and glycolic acids. These acids are eventually reduced by the Kreb's cycle to carbon dioxide and water, which the body can easily expel.
Regular AA-BB type amino acid based bio-analogous poly(ester amides) (PEAs) consisting of nontoxic building blocks, such as hydrophobic α-amino acids, aliphatic α,ω-diols, and aliphatic (fatty) dicarboxylic acids, have been investigated as biomaterials for drug release and tissue engineering applications (G. Tsitlanadze et al. J. Biomater. Sci. Polymer Edn, (2004) 15: 1-24). The combination in PEAs and PEURs of controlled enzymatic degradation and low rates of nonspecific hydrolysis makes these polymers attractive for drug delivery applications. In particular, PEAs appear to be blood and tissue compatible with advantageous properties for cardiovascular applications (K. DeFife et al. Transcatheter Cardiovascular Therapeutics—TCT 2004 Conference. Poster presentation. Washington D.C. (2004)).
In most drug-eluting applications, the drug is physically matrixed by dissolving or melting with a polymer. Another approach has also been reported in which a drug is chemically attached as a side group to a polymer.
If a drug or other therapeutic agent is covalently incorporated into a biodegradable polymer, a therapeutic polymer is formed. Such compositions represent synthetic polymers that combine therapeutic or palliative bioactivity with desirable mechanical and physical properties, and degrade into useful therapeutic active compounds. In other words, the compositions have the activity of a drug, but have the physical properties of a material. Recently, new therapeutic polyesters, polyamides, and poly(ester anhydrides) were reported, wherein non-steroidal anti inflammatory drugs (NSAIDs) were incorporated into a polymer backbone (R. C. Schmeltzer et al. Biomacromolecules. (2005) 6(1):359-367). In such compositions, drug release is directly dependent on the hydrolytic or enzymatic cleavage of polymer-drug binding groups. One of the advantages of a “backbone as a drug” polymer is that a high amount of drug or therapeutic compound can be incorporated into the structure.
Despite these advances in the art, there is a need for more and better polymer compositions and medical implants containing such compositions, wherein therapeutic molecules, such as drugs and other bioactive agents, are covalently attached to the polymer or incorporated into the backbones of polymer and release of the bioactive agents at a controlled rate is combined with desirable mechanical and physical properties of the polymer compositions.